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PERSPECTIVE OPEN Drugs, sleep, and the addicted brain

Rita J. Valentino1 and Nora D. Volkow 1 Neuropsychopharmacology (2020) 45:3–5; https://doi.org/10.1038/s41386-019-0465-x

The neurobiology of sleep and substance abuse interconnects, opioid-withdrawal signs, including the hyperarousal and insomnia such that alterations in one process have consequences for the associated with withdrawal [9]. Notably, α2-adrenergic antagonists other. Acute exposure to drugs of abuse disrupts sleep by (lofexidine and clonidine) that inhibit LC discharge are clinically affecting sleep latency, duration, and quality [1]. With chronic used for the attenuation of opioid and alcohol withdrawal to administration, sleep disruption becomes more severe, and during reduce peripheral symptoms from sympathetic activation, such as abstinence, insomnia with a negative effect prevails, which drives tachycardia, as well as central symptoms, such as insomnia, drug craving and contributes to impulsivity and relapse. Sleep anxiety, and restlessness. Their utility in suppressing symptoms impairments associated with drug abuse also contribute to during protracted abstinence, such as insomnia, along with its cognitive dysfunction in addicted individuals. Further, because associated adverse consequences (irritability, fatigue, dysphoria, sleep is important in consolidation and the process of and cognitive impairments) remains unexplored. extinction, sleep dysfunction might interfere with the learning of Like LC–NE , the raphe nuclei (including the dorsal non-reinforced drug associations needed for recovery. Notably, raphe nucleus—DRN) serotonin (5-HT) neurons modulate sleep current medication therapies for opioid, alcohol, or nicotine and wakefulness through widespread forebrain projections. The addiction do not reverse sleep dysfunctions, and this may be an role of this system in sleep is complex. Raphe nucleus lesions obstacle to recovery [2, 3]. Whereas exposure to drugs of abuse is trigger insomnia [10, 11], and during the awake state, the causal to sleep dysfunctions that further promote chronic use, cumulative 5-HT, released from the raphe into the basal forebrain sleep disorders in turn are risk factors for substance abuse and (including the nucleus basalis, which is the main cholinergic input their severity can predict the prognosis of substance use disorders to the cortex, and regulates ), is believed to serve as a (SUD) [4]. Sleep disruption results in a cumulation of risk factors sleep-promoting factor [11]. However, 5-HT neurons are active that drive drug abuse, including increasing the sensitivity to pain, during waking, decrease their activity during slow-wave sleep, and acting as a stressor, and biasing toward a negative effect. cease firing during REM sleep, as is the case for LC–NE neurons Recognizing and treating sleep disorders may be an important [12, 13]. Notably, DRN-5-HT neurons are implicated in the arousal preventive measure against future drug misuse and SUD. Despite from sleep in response to hypercapnia [14], which is impaired convergent evidence linking sleep and substance abuse, and the during opioid-induced overdoses, and further work is required to therapeutic potential that can emerge from elucidating the assess how to target the serotonin system as a way to prevent biology underlying this link, this has been a relatively neglected opioid-induced overdoses or to improve outcomes when nalox- area of research. A first step in advancing this area is to identify one cannot completely reverse them (Table 1). how the circuits and substrates that regulate sleep and arousal Like the LC–NE and DRN-5-HT systems, the (HA) intersect with those that mediate reward and also how they are neurons of the tuberomammillary nucleus form another diffusely targeted by drugs of abuse. projecting arousal system that is active during waking only and The locus coeruleus (LC)–norepinephrine (NE) system is a these neurons are activated by opioids, which can further diffuse forebrain-projecting system that is involved in arousal and contribute to sleep disruption associated with chronic opioid also is a primary target of drugs of abuse, including nicotine, use. HA promotes arousal through activation of cortical and basal stimulants, opioids, and cannabinoids. LC–NE neuronal activity is forebrain neurons, effects that are primarily mediated by H1 positively correlated to the state of arousal, and LC neurons are receptors [15, 16]. Thus, the H1 receptor may be an alternate most active during waking and are off during REM sleep [5]. target for treating sleep dysfunction associated with abstinence. Selective LC activation is sufficient to elicit cortical arousal, and In contrast to the LC–NE and DRN-5-HT neurons, midbrain conversely, selective LC inhibition prevents cortical activation by dopamine (DA) neurons were not considered to be sleep-related, stressors, indicating that this system is important in regulating because they show little change in discharge rate during the cortical arousal in response to stressors and other salient stimuli sleep/wake cycle other than bursting during paradoxical sleep. [6, 7]. The stress-related neuropeptide, corticotropin-releasing However, the wake-promoting actions of drugs that enhance DA factor (CRF), mediates stress-induced LC excitation, and endogen- signaling are widely recognized and used for clinical purposes ous opioids that innervate the LC exert an opposing effect [17, 18]. Transgenic modifications that enhance DA neurotrans- that may serve to restrain excessive activation and promote mission in mice, such as deletion of the DA transporter gene, recovery after stress termination [8]. Opioid tolerance would be result in increased wakefulness [19], whereas deletion of DA D2 expected to enhance stress-induced activation of this arousal receptors (D2R) decreases wakefulness [20]. Further, recent system, and promote a cycle of drug seeking to tone down the optogenetic studies demonstrated that activation of DA neurons excessive response. LC neurons are robustly activated during in the ventral tegmental area (VTA) but not substantia nigra opioid withdrawal and this has implicated the LC–NE system in increases wakefulness [21]. These arousal effects are mediated by

1National Institute on Drug Abuse, National Institutes of Health, 6001 Executive Blvd, Rm 4269, MSC 9555, Bethesda, MD 20892, USA Correspondence: Rita J. Valentino ([email protected]) Received: 25 June 2019 Accepted: 2 July 2019 Published online: 16 July 2019

© The Author(s) 2019 Drugs, sleep, and the addicted brain RJ. Valentino and ND. Volkow 4

Table 1. Predominant effects of targets of various drugs in sleep and arousal and their typical effects during intoxication and withdrawal Orexin Neurotransmitter Drug Intoxication Abstinence LC-NE LDT-ACh NE Stimulants Enhanced Reduced during early VTA-DA Arousing Opioids Reduced stages of withdrawal Alcohol Reduced Hyperexcitable DRN-5-HT Hyperexcitable NAc 5-HT Stimulants Enhanced Reduced TMN-HA Arousing/sedating Ecstasy Enhanced NBM-ACH Enhanced DA Stimulants All drugs D2R, DAT, and DA Arousing Opioids enhance DA release are Nicotine downregulated Cannabis Alcohol Fig. 1 Schematic depicting efferent projections of lateral hypotha- Histamine Opioids Enhanced lamic orexin neurons. The orexin system is positioned to influence Arousing Alcohol Reduced cognitive function, arousal, and reward. Orexin neurons have broad Nicotine forebrain projections. Cortical projections may modulate cognitive Nicotine Enhanced Tolerance aspects of substance use behavior such as decision-making. In Arousing addition, they project to arousal-related nuclei, including the locus Orexin Cocaine Enhanced Upregulated coeruleus (LC), which expresses norepinephrine (NE), dorsal raphe Arousing Opioids Enhanced Upregulated nucleus (DRN), which expresses serotonin (5-HT), lateral dorsoteg- Mu opioids Opioids Enhanced Tolerance of MOR mental nucleus (LDT), which expresses (ACh), tuber- Sedating Nicotine Enhanced omammillary nucleus (TMN), which expresses histamine (HA), and Alcohol Enhanced nucleus basalis of Meynert (NBM), which expresses ACh. These nuclei in turn have diffuse projections throughout the forebrain.

1234567890();,: Adenosine Reduced Tolerance Orexin neuronal projections to the ventral tegmental area (VTA) and Sedating (NAc) are poised to modulate reward and to Cannabinoids Cannabis Enhanced Downregulation make rewarding stimuli arousing Sedating Because the effects of a neurotransmitter on arousal and sleep may differ depending on the brain region it targets, in some instances, the effects are dreams and poor sleep quality that is predictive of relapse [27]. mixed as is the case for serotonin. Also, the effects can differ during early ECS disruption with chronic marijuana use is likely to underlie the versus protracted withdrawal, such as is the case for cocaine that leads to long-lasting insomnia commonly observed during abstinence in enhanced sedation that can last up to 3–4 weeks post withdrawal to then cannabis abusers. be followed by protracted insomnia The orexin system that derives from the posterior lateral is like the LC–NE, DRN-5-HT, and TMN–HA systems in that the cells only fire during waking and are silent during sleep phases [28]. It is unique in being essential for sustaining the VTA projections to the nucleus accumbens, because optogenetic waking state, as its disruption in patients with narcolepsy leads to activation of DA terminals here, but not in other terminal regions, periodic and abrupt interruptions of the conscious state. The also promoted wakefulness. Therefore, this specific DA circuit is a cluster of orexin neurons in the hypothalamus is a node that links node that regulates the rewarding effects of drugs of abuse and to the other arousal-related nuclei, including basal forebrain one that mediates arousal, including that elicited by salient and cholinergic neurons, TMN–HA neurons, DRN-5-HT neurons, rewarding stimuli. VTA–DA neurons, lateral dorsal tegmental cholinergic neurons, The endogenous cannabinoid system (ECS) that signals through and LC–NE neurons (Fig. 1). It is poised to orchestrate a cannabinoid CB1 and CB2 receptors, which are targets of synchronous activation of multiple arousal systems. In addition marijuana, is also involved in circadian rhythm and the regulation to its role in arousal, orexin has a role in the rewarding effects of of the sleep–wake cycle [22, 23]. Acutely, cannabis is sleep- drugs of abuse, including those of opioids [29]. For example, promoting and decreases latency, increases sleep time, increases narcoleptics that have low orexin levels do not abuse opioids and slow-wave sleep, and decreases REMs [1, 23]. Consistent with this, mice with genetic deletion of orexin show decreased opioid- CB1 antagonists increase wakefulness and decrease slow-wave addiction potential, implicating orexin in the initial rewarding sleep and REMs and conversely, the endogenous CB1 agonist, effects of opioids [29]. Orexin neurons are activated by reward and anandamide enhances slow-wave sleep and REM [24]. The effects project to the DA neurons in VTA that innervate the nucleus of CB1 signaling may be mediated through the sleep-promoting accumbens and mediate reward, which they also influence via molecule, adenosine because doses of anandamide that promote their direct projections to it. Chronic opioid exposure upregulates sleep increase adenosine release in the basal forebrain [25]. orexin in humans and rodents [30]. Postmortem brains of heroin Notably, adenosine is the target of caffeine, which is an adenosine users showed increases in orexin numbers in the lateral receptor antagonist that is widely used to increase arousal. hypothalamus and reverse translation studies verified that chronic Another potential mechanism for the sleep-promoting effects of opioid administration in rodents also increased the number of endocannabinoids is through their opposing regulation of orexin neurons in their . The upregulation of neuronal activity in the lateral hypothalamus, inhibiting the orexin would be expected to create a state of hyperarousal and activity of arousal-promoting orexin neurons (see below), while may underlie the insomnia observed both in treated and non- increasing the activity of sleep-promoting melanin concentrating treated opioid users. Preclinical studies, demonstrating that orexin hormone neurons [26]. microinjection into the VTA increases cocaine self-administration With chronic use, tolerance occurs to the sleep-enhancing and reinstates cocaine-conditioned place preference, also impli- effects of cannabis, and abstinence is characterized by unusual cate orexin in cocaine’s rewarding effects. It has been suggested

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